Sjogren's syndrome, one of the connective tissue autoimmune diseases, presents clinically as a loss of exocrine secretory function due to autoaggression primarily against the salivary and lacrimal glands. The mechanism(s) underlying the tissue specific destruction of target organs in Sjogren's syndrome is not understood at the present time. Our studies have now established the NOD (non-obese diabetic) and NOD.B10.H2b mice as the best animal models for secondary and primary Sjogren's syndrome, respectively. To date, the NOD mouse remains the only animal identified to develop the corresponding pathophysiology of salivary gland secretion loss and lacrimal tear production in conjunction with the histological observation of lymphocytic infiltration of the exocrine tissues. Results of our studies have novel implications in how we define the autoimmune disease paradigm with the observation of exocrine gland cellular alterations which develop in the absence of a functional lymphocyte system (NOD-scid). Autoimmune diseases, such as IDDM, IBD, and Hashimoto's thyroiditis, similar to our studies in both the NOD-scid and NOD parental strain, indicate nonimmune factors, as a consequence of genetically programmed loss of glandular differentiated function or homeostasis, appear to contribute to initiating the disease process. Using a second congenic strain lacking B-cells (NOD.Igu null), the loss of secretory function was shown to be independent of T-cells but not autoantibodies. To elucidate further the mechanism(s) responsible for the loss of exocrine target tissue function of Sjogren' s syndrome-like disease in the NOD model, the following specific aims are proposed: 1. Define the role of regulatory effector cytokines modulating the humoral response in autoimmune exocrinopathy through the analysis of specific knockout mice; and 2. Define the components of the humoral immune response promoting exocrine gland destruction, using the NOD mouse models of Sjogren's syndrome. These studies will expand on our novel observations which established the NOD mouse as an appropriate model for the study of Sjogren's syndrome-like pathology by analyzing the role of the humoral immune system components and effector cytokines in the precipitation of exocrine tissue dysfunction. By using a global approach to the analyses of this autoimmune disease involving a coordinated evaluation of both the lacrimal and salivary glands, the results from this research will provide innovative insights into the mechanism(s) triggering autoimmune attack on specific tissues and further suggest novel strategies for the control of this tissue destruction.